Determination of the mechanistic targets of metformin

项目摘要 糖尿病影响着超过3000万美国人，占人口的9.4%。 糖尿病导致血糖水平升高。随着时间的推移，体内高葡萄糖的存在 导致各种组织损伤。美托洛尔是一种FDA药物，通常用作一线治疗， 2型糖尿病的治疗它的主要作用是使组织对胰岛素更敏感， 增强由胰腺产生的胰岛素的作用以稳态地降低血糖水平。 然而，重要的是，Metabolic还延长寿命，并延迟从酵母到衰老的开始。 哺乳动物在高等生物中，它还可以降低心血管疾病的风险， 肿瘤生长令人惊讶的是，鉴于其自1958年以来在人类中的临床应用， 其潜在的广泛健康益处尚不清楚。该催化剂项目旨在 首次阐明了Metabolic的直接细胞蛋白靶点。我们令人鼓舞的初步 数据显示，我们可以将尖端的蛋白质组学方法应用于这种无偏见的结合事件， 路上了在这个项目中，我们希望将这种非常有前途的方法扩展到各种生物。 通过在多种遗传学上不同的模式生物中鉴定代谢酶的分子靶点， （酵母、蠕虫、苍蝇、老鼠和人类），我们将能够找到至关重要的蛋白质， 同时筛选出非特异性结合剂。我们将对发现的目标进行机械测试 通过使用各种检测方法进行功能丧失和获得实验，这些实验将根据项目进行调整 预付款。在验证了少量强的候选Metabolic结合蛋白后，我们将测试 这些有希望的候选人在哺乳动物中，通过使转基因小鼠携带相关基因缺失， 编码这些蛋白质的基因。我们预计，识别特定的机械代谢 这些靶点将有助于开发治疗糖尿病和促进健康老龄化的新疗法。 这两个目标都与NIDDK和更广泛的NIH的核心使命密切相关。

PROJECT SUMMARY Diabetes affects over 30 million Americans, which represents a staggering 9.4% of the population. Diabetes causes an elevated blood glucose level. Over time, the presence of high glucose in the body results in damage to various tissues. Metformin is an FDA drug commonly used as a first line therapy for the treatment of Type 2 Diabetes. It mainly acts to make tissues more sensitive to insulin, thereby enhancing the effects of insulin produced by the pancreas to homeostatically lower blood glucose levels. Importantly, however, Metformin also prolongs lifespan and delays the onset of aging from yeast to mammals. In higher organisms, it additionally reduces the risk of cardiovascular disease and inhibits tumor growth. Astoundingly, given its clinical use in humans since 1958, the exact molecular mechanisms underlying its wide-ranging health benefits are unknown. This Catalyst project is directed towards elucidating the direct cellular protein targets of Metformin for the first time. Our encouraging preliminary data shows that we can apply cutting-edge proteomics approaches to such binding events in an unbiased way. In this project, we wish to extend this extremely promising approach to a diverse range of organisms. By identifying molecular targets of Metformin in a variety of phylogenetically different model organisms (yeast, worms, flies, mouse, and humans), we will be able to home in on proteins of crucial importance, while simultaneously screening out non-specific binders. We will mechanistically test discovered targets by loss- and gain-of-function experiments using various assays, which will be adapted as the project advances. After validation of a small number of strong candidate Metformin binding proteins, we will test these promising candidates in mammals by making transgenic mice harboring deletions in the relevant genes coding for these proteins. We anticipate that the identification of specific mechanistic Metformin targets will facilitate the development of novel therapeutics to treat diabetes and promote healthy aging. Both of these goals are closely aligned with the core missions of NIDDK, and the wider NIH.